The Clinical Genetics Branch (CGB) is NCI's base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer; Developing comprehensive management strategies for high-risk individuals and families; and Training the next generation of clinical cancer genetics investigators.Hereditary Breast/Ovarian Cancer (HBOC) is based on a prospective cohort of 33 BRCA mutation-positive families with extensive clinical/epidemiologic data and biological samples. Clinical activity related to this study has ended, but its biospecimens continue to be used in multiple translational research projects. The most recent analysis of breast cancer risk in these prospectively-monitored families indicates that mutation-negative women from these mutation-positive families have risks that are similar to those seen in the general population. To date, 20 clinical manuscripts have been published and 40 reports plus 8 manuscripts under review (in collaboration with the international consortium CIMBA) elucidating genetic modifiers of BRCA-related breast and ovarian cancer penetrance have been published. Inherited Bone Marrow Failure Syndromes (IBMFS) Study targets Fanconi anemia (FA) and related disorders which include high risk of aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. We have enrolled 1722 members from 406 IBMFS families. Major findings include quantitative estimates of FA- and dyskeratosis congenita (DC)-related cancer risks, identifying the striking similarity in cancer risks in these 2 disorders, expanding the clinical phenotype of these syndromes, and identifying very short telomeres as pathognomonic for DC. Under a Fanconi Anemia Research Foundation grant, we are writing a report on immune function in FA patients. We collaborated on development of an in vitro assay for pathogenicity of missense variants of unknown significance in FANCD1/BRCA2. We have identified four (TINF2, WRAP53, RTEL1, ACD) of the 10 known dyskeratosis congenita genes, and provided the first evidence that the DC phenotype includes a high risk of neuropsychiatric disorders. We have analyzed the North American Diamond- Blackfan Registry (DBAR) and documented for the first time significant risks of cancer, particularly osteosarcoma, in DBA. Familial Testicular Cancer We have enrolled 733 consented members from 151 newly-ascertained families. Recent findings include confirmation of our association between missense variants in PDE11A and TGCT risk, both familial and sporadic, determining that relatives of men with sporadic bilateral TGCT are at a 12-fold increase in TGCT risk, identification of 16 of the 40 TGCT GWAS risk SNPS, determined that FTGCT is a site-specific cancer syndrome, found an association between in utero exposure to DES and FTGCT, developed a polygenic risk score model that, when combined with cryptorchidism, identifies a subgroup of subjects who are at 50-fold greater TGCT risk. The Li-Fraumeni Syndrome (LFS), originally identified by DCEG investigators 40 years ago, is a rare, inherited disorder caused by germline TP53 mutations, with increased risks of early-onset bone and soft tissue sarcomas, breast, adrenal and brain cancer. We have initiated a new LFS study which has enrolled 600 members from 180 families, and is providing genetic counseling and testing in search of new LFS genes in the 30% of LFS patients with a TP53 mutation, investigating novel cancer screening modalities (e.g., total body MRI), attempting to identify genetic modifiers of risk, and studying cancer risk-reduction strategies. We published the proceedings of an international workshop (November 2010) that resulted in formation of a new international LFS Research Consortium and the first LFS patient advocacy group. The risks of first and subsequent cancers amongst TP53 mutation carriers in our cohort are very high and nearly 100% of participants have had at least one cancer by age 70 years. The cumulative cancer incidence was 50% by age 31 years in TP53+ women and 46 years in men. Ongoing studies seek to better understand the molecular characteristics of LFS-associated tumors, genetic and environmental modifiers, and the optimal cancer screening regimen. Familial Pleuropulmonary Blastoma (PPB) is a newly-described syndrome caused by germline mutations in DICER1; it represents the first known cancer predisposition syndrome caused by altered microRNA biogenesis. To date, we have enrolled 400 members from 80 PPB families, evaluated 130 subjects at the NIH Clinical Center and performed DICER1 mutation testing on 150 subjects. Leveraging an NIH Bench-to-Bedside award, we have formed a collaboration with the research group which discovered DICER1, with whom we are doing a detailed clinical phenotype and cancer risk quantification study of this rare, novel syndrome. A review of the PPB syndrome was published online in GeneReviews, and a report describing PPB-related nasal chondromesenchymal hamartoma was also published. Publications describing 350 registry-based PPB cases, the first 25 PPB families evaluated, and an analysis of PPB-related thyroid neoplasia are in press as well. Neurofibromatosis 1 is a classic hereditary cancer susceptibility disorder. We are further defining its phenotype and seeking genetic modifiers of NF1 penetrance. We have shown that Jaffe-Campanacci syndrome is allelic to NF1. We have identified specific genetic variants that modify the risk of developing NF1-related caf-au-lait macules, an important proof-of-principle observation, and demonstrated that loss of the wild-type NF1 allele is the primary driver of plexiform neurofibroma tumorigenesis.Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer is a vital component of each study in CGB's research portfolio, which has yielded more than 50 peer-reviewed publications. We have extended the application of a new genetic counseling tools, e.g., the Colored Ecogenetics Relationship Map, from HBOC to FTGCT, applied novel analytic strategies, such as social network analysis, analyzed the variables associated with choosing surgery or screening in GOG-199, assessed determinants of bone marrow transplant decision-making within FA families, and explored the impact of ambiguous and false-positive screening test results on mood and screening behavior of BRCA1/2 mutation carriers. In our Rare Familial Cancer Syndromes WES sequencing project, we have etiologically implicated CBL mutations in juvenile JMML, CEBPA in familial AML, and BRAF mutations in familial hairy cell leukemia. We have also shown that Dubowitz syndrome is a syndrome complex of multiple genetically-distinct, phenotypically overlapping disorders in which germline LIG4 mutations play an etiologic role. This approach is also being applied to studies of familial and sporadic bladder cancer, gene discovery in the inherited bone marrow failure syndromes, and pediatric cancers.